Understanding the evolutionary origins and global spread of Plasmodium vivax can provide critical insight into the origin of drug resistance alleles and other important genetic differences in contemporary parasite populations. Unfortunately, nearly everything we know about African P. vivax comes from ape feces, with amplification of a few specific genes. This approach provides an incomplete and likely biased picture of population structure and the evolutionary origins of vivax due to the relatively small sequencing space analyzed. The goal of this project is to characterize the P. vivax population in Central Africa and trace migration of this population through the Horn of Africa and into Southeast Asia. Malaria remains a public health challenge through most of the tropical and subtropical regions of the world. Plasmodium vivax is the most widespread of the species of malaria causing parasites, causing nearly 14 million clinical cases annually with nearly 2.5 billion people at risk of infection. Vivax malaria is highly prevalent In the Horn of Africa, South America and Southeast Asia. However, it was historically assumed to not exist in Central and Southern Africa due to the nearly uniform lack in Indigenous African populations of the Duffy antigen receptor for chemokines (DARC), a primary receptor for red blood cell invasion by the parasite. However, over the last decade it has become clear that vivax transmission Is occurring in these regions and is not completely inhibited by the lack of DARC. These findings have raised many questions about the history of P. vivax and its evolutionary origins. P. vivax was recently detected by our group in DARC-negative humans in Central Africa. This discovery opens an unexpected and unprecedented window into studying the likely source population for global P. vivax. The goals of this project are: 1) Identification of risk factors for P. vivax infection based on the 2013 Demographic Health Survey (OHS) in the Democratic Republic of Congo, 2) Characterization of genetic variation and demographic properties of the human P. vivax population in Central Africa, 3) Reconstruction of the out-of-Africa migration of P. vivax into Southeast Asia, and 4) Reconstruction of the evolution of drug resistance alleles in P. vivax populations. The identification of human P. vivax infection in Central Africa allows, for the first time, a complete reconstruction of its evolutionary origins and subsequent history of migration.